This invention relates to compounds useful as muscle relaxants. In one of its more particular aspects, the invention relates to a series of alkoxy- and acyloxy-substituted aralkyl and aralkenyl bis quaternary ammonium derivatives of cyclic alkanol diesters. This invention also relates to methods for the preparation and use of such compounds as muscle relaxants and to pharmaceutical compositions containing such compounds.
During surgery it is preferred that the muscles of the patient be as relaxed as possible. Although general anesthesia renders the patient unconscious, it only rarely provides sufficient skeletal muscle relaxation. A variety of muscle relaxant agents, also known as neuromuscular blocking agents, are used for muscle relaxation during surgery. One muscle relaxant used frequently in the past is succinylcholine, which has a very rapid onset and short duration of clinical action. However, succinylcholine elicits muscle membrane xe2x80x9cdepolarizationxe2x80x9d which makes this compound less desirable. Furthermore, it may produce serious side effects.
Several other so called xe2x80x9cnon-depolarizingxe2x80x9d muscle relaxants are known and used in anesthesia and surgery. These chemically diverse non-depolarizing muscle relaxants include, among others: tubocurarine, pancuronium, atracurium, cisatracurium, vecuronium, mivacurium and rocuronium. The common structural feature of these compounds is one or usually two quaternary nitrogen atoms. They are all clinically acceptable because they produce only mild or no side effects. However, their onset of action is too slow and their duration of action is too long. Thus, these agents, without exception, fall short of the requirements of an xe2x80x9cidealxe2x80x9d surgical muscle relaxant.
Hungarian Patent No. 142,597 issued on Sep. 15, 1955, discloses a series of compounds having a pair of tropine moieties bound by an ester linkage to an aliphatic or aromatic diacid. The nitrogens on both tropines are quaternized with alkyl or unsubstituted or monosubstituted benzyl groups.
Certain naturally occurring alkaloids consist of dicarboxylic acid esters of azabicyclo alkanols, such as belladonnine, which is a bis tropinester, and thesine, which is a bis oxymethyl pyrrolizidine ester. Only the ethyl quaternary derivative of belladonnine and the methyl quaternary derivative of thesine have been reported as muscle relaxants.
Some other neuromuscular blocking agents that include pairs of quaternary nitrogens as part of a tropane ring system have been reported in the literature. In these compounds tropinyl moieties are joined by bridging the two quaternary nitrogens. U.S. Pat. No. 2,746,964 (1953) discloses dicarboxylic acid esters of 3-piperidinol and their alkyl quaternary derivatives.
It is an object of the present invention to provide new and improved muscle relaxants which are characterized by very rapid onset and short duration of neuromuscular blocking action.
In our research for the xe2x80x9cidealxe2x80x9d muscle relaxant we have discovered that in general, di- or poly- alkoxy- or acyloxy-substituted aralkyl and aralkenyl quaternary ammonium derivatives of cyclic aminoalkanol diesters either exhibited less side effects such as decreased blood pressure and increased heart rate or greater potencies than other agents with alkyl, unsubstituted aralkyl, or monosubstituted aralkyl quaternary groups. In particular, such alkoxy- and acyloxy-substituted aralkyl and aralkenyl quaternary derivatives of cyclic aminoalkanol diesters were much more rapidly and shorter acting than any xe2x80x9cnondepolarizingxe2x80x9d muscle relaxant compound hitherto known. This discovery was entirely unexpected and unpredicted and thus forms the basis of this invention.
This invention consists of a series of di- or poly-alkoxy- or acyloxy-substituted aralkyl and aralkenyl bis-quaternary ammonium derivatives of cyclic alkanol esters of dicarboxylic acids as neuromuscular relaxants, methods of making and using them, and pharmaceutical compositions containing them.
The first aspect of this invention is a group of compounds 1/a, having the general formula illustrated below: 
A second aspect of this invention is a group of compounds 1/b, having the general formula illustrated below: 
A third aspect of this invention is a group of compounds 1/c, having the general formula illustrated below: 
where A is alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkenedicarbonyl, polycycloalkanedi-carbonyl, polycycloalkenedicarbonyl, aromatic dicarbonyl, substituted alkanedicarbonyl, substituted alkenedicarbonyl, substituted alkynedicarbonyl, substituted bicycloalkanedicarbonyl, substituted bicycloalkenedicarbonyl, or substituted aromatic dicarbonyl; R1 and R1xe2x80x2 are di- or polysubstituted aralkyl or aralkenyl in which at least one of the substituents is alkoxy or acyloxy; R2 and R2xe2x80x2 are alkyl or alkenyl; n is 0, 1, or 2; m is 0, 1, or 2; p is 0, 1, or 2; R3 and R3xe2x80x2 are H, CH3, or lower alkyl; R4 and R4xe2x80x2 are H, CH3, or lower alkyl; R3 and R4 can also be xe2x80x94(CH2)gxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94(CH2)hxe2x80x94Oxe2x80x94(CH2) kxe2x80x94, -epoxy-, orxe2x80x94(CH2)hxe2x80x94Sxe2x80x94(CH2)kxe2x80x94, where g is 2, 3, 4, or 5, h is 1 or 2, and k is 1 or 2; and R3xe2x80x2 and R4xe2x80x2 can also be xe2x80x94(CH2)gxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94(CH2)hxe2x80x94Oxe2x80x94(CH2)kxe2x80x94, 
or xe2x80x94(CH2)hxe2x80x94Sxe2x80x94(CH2)kxe2x80x94, where g is 2, 3, 4, or 5, h is 1 or 2, and k is 1 or 2; X is a pharmaceutically acceptable anion; R1 and R1 xe2x80x2 can be the same or different; likewise R2 and R2xe2x80x2, R3 and R3xe2x80x2, and R4 and R4xe2x80x2 can be the same or different.
A fourth aspect of this invention is the method of use of the compounds of the general formulae 1/a-1/c as neuromuscular relaxants.
A fifth aspect of this invention is a pharmaceutical composition, including the compounds of general formulae 1/a-1/c and a pharmaceutically acceptable excipient.
Definitions
As used herein, the term xe2x80x9calkylxe2x80x9d refers to a hydrocarbon radical having from 1 to 20 carbon atoms. In this invention alkyl can be non-substituted, for example, methyl, butyl, octyl, and dodecyl.
As used herein, the term xe2x80x9calkenylxe2x80x9d refers to any hydrocarbon radicals having from 1 to 20 carbon atoms that includes at least one carbon-carbon double bond at any position. Examples include ethenyl, 2-butenyl, 5-octenyl, and 2,10-dodecenyl.
As used herein, the term xe2x80x9calkynylxe2x80x9d refers to hydrocarbon radicals having from 1 to 20 carbon atoms that includes at least one carbon-carbon triple bond at any position. Examples include acetylenyl, 2-butynyl, 5-octynyl, and 1,7-decanediynyl.
As used herein, the term xe2x80x9carylxe2x80x9d refers to aromatic hydrocarbon radicals. Examples include phenyl, naphthyl, and anthracyl.
As used herein, the term xe2x80x9caralkylxe2x80x9d refers to aryl hydrocarbon radicals including an alkyl portion as defined above. Examples include benzyl, phenylethyl, and 6-napthylhexyl.
As used herein, the term xe2x80x9caralkenylxe2x80x9d refers to aryl hydrocarbon radicals including an alkenyl portion, as defined above. Examples include styryl, 3-benzylpropenyl, and 6-naphthyl-2-hexenyl.
As used herein, the term xe2x80x9ccycloalkylxe2x80x9d refers to an alkyl that has its carbon atoms arranged into a ring. Examples include cyclohexyl, cyclobutyl, and cyclododecyl.
As used herein, the term xe2x80x9ccycloalkenylxe2x80x9d refers to an alkenyl that has its carbon atoms arranged into a ring. Examples include cyclohexenyl and 1,5-cyclododecadienyl.
As used herein, the term xe2x80x9cbicycloalkylxe2x80x9d refers to an alkyl that has its carbon atoms arranged into two rings. Examples include decahydronaphthyl, norbornyl, and bicyclo [2.2.2] octyl.
As used herein, the term xe2x80x9cbicycloalkenylxe2x80x9d refers to an alkenyl that has its carbon atoms arranged into two rings. Examples include norbornenyl and 1,2,3,4,5,6,7,8-octahydronaphthyl.
As used herein, the term xe2x80x9cpolycycloalkylxe2x80x9d refers to an alkyl that has its carbon atoms arranged into three or more rings.
As used herein, the term xe2x80x9cpolycycloalkenylxe2x80x9d refers to an alkenyl that has its carbon atoms arranged into three or more rings.
As used herein, the term xe2x80x9csubstitutedxe2x80x9d refers to a hydrocarbon radical selected from the groups alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, polycycloalkyl, polycycloalkenyl, and all as defined above, where one or more hydrogens have been replaced with alkyl, fluoride, chloride, bromide, iodide, hydroxy, mercapto, alkoxy, acyloxy, alkylthio, arylthio, acetamido, amino, or nitro group(s). Also the term xe2x80x9csubstitutedxe2x80x9d refers to a hydrocarbon radical selected from the groups alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, polycycloalkyl, polycycloalkenyl, and all as defined above, where one or more carbons have been replaced with oxygen, sulfur, nitrogen, or silicon atom(s).
In case of the quaternizing aralkyl or aralkenyl groups, xe2x80x9cdisubstituted or polysubstitutedxe2x80x9d refers to two or more substituents, one or more of which shall be alkoxy or acyloxy and the other(s) shall be one or more identical or different substituents selected from the groups: alkyl, alkenyl, aryl, aralkyl, halogen, hydroxy, mercapto, alkoxy, aryloxy, acyloxy, acetamido, amino, alkylthio, arylthio, imino or nitro groups which replace two or more hydrogen atoms of the aralkyl or aralkenyl moiety.
As used herein, the term xe2x80x9calkyl-cycloalkylxe2x80x9d refers to a hydrocarbon radical including an alkyl and a cycloalkyl group. Examples include 3-methylcyclohexyl and 4-hexylcycloheptyl.
As used herein, the term xe2x80x9calkanedicarbonylxe2x80x9d refers to a radical that includes an alkyl as defined above and two carbonyl groups. Examples include succinyl, glutaryl, sebacyl, 1,11-dicarboxyundecanyl, and the like.
As used herein, the term xe2x80x9calkenedicarbonylxe2x80x9d refers to a radical that includes at least one carbon-carbon double bond and two carbonyl groups. Examples include 1,3-discarboxypropenyl, 1,6-dicarboxy-3 -hexenyl, and traumatyl (1,10-dicarboxy-2-decenyl).
As used herein, the term xe2x80x9calkynedicarbonylxe2x80x9d refers to a radical that includes at least one carbon-carbon triple bond and two carbonyl groups. Examples include 1,2-dicarboxypropynyl, 1,6-dicarboxy-2-hexynyl, and the like.
As used herein, the term xe2x80x9cbicycloalkanedicarbonylxe2x80x9d refers to a radical that includes bicycloalkenyl as defined above and two carbonyl groups. Examples include 5-norbornane-2,3-dicarbonyl, dicahydronaphthalene-1,5-dicarbonyl, and 9,10-dihydro-9,10-ethanoanthracene-11,12-dicarbonyl.
As used herein, the term xe2x80x9cbicycloalkenedicarbonylxe2x80x9d refers to a radical that includes bicycloalkenyl as defined above and two carbonyl groups. Examples include 3,6-endomethylene-1,2,3,6-tetrahydrophthaloyl and 1,2,3,4,5,6,7,8-octahydronaphthalene-1,5-dicarbonyl.
As used herein, the term xe2x80x9caromatic dicarbonylxe2x80x9d refers to a radical that includes an aromatic group substituted with two carbonyl groups. Examples include phthalyl, terephthalyl, 1,4-dicarboxynaphthyl, and the like.
As used herein, the term xe2x80x9cacyloxyxe2x80x9d refers to RC(O)Oxe2x80x94 in which R is a normal or substituted hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, or bicycloalkenyl. Examples include acetoxy, propionyloxy, 2,3-difluorobutyryloxy, benzoyloxy, cyclopropylacetoxy and chloroacetoxy.
As used herein, the term xe2x80x9ctropinexe2x80x9d refers to tropine (8-methyl-8-azabicyclo [3.2.1]octan-3xcex1-ol), also known as alpha or endo tropine, and pseudotropine (8-methyl-8-azabicyclo[3.2.1]octan-3xcex2-ol), also known as beta or exo tropine, dependent on the configuration of the hydroxy group attached to the C3 atom of tropine.
As used herein, the term xe2x80x9cgranatanolxe2x80x9d refers to 9-methyl-9-azabicyclo[3.3.1]nonan-3xcex1-ol or 9-methyl-9-azabicyclo[3.3.1]nonan-3xcex2-ol, and also the term xe2x80x9cgranataninexe2x80x9d refers to 9-methyl-9-azabicyclo[3.3.1]nonane. It will of course be realized that the nitrogen atom of tropine and of granatanol is already methyl substituted. Therefore, when the tropine or granatanol nitrogen is referred to as substituted, as in N-methyltropinium iodide, it will be understood that the nitrogen is a quaternary nitrogen and the halide is present for charge balance.
As used herein, the term xe2x80x9cpharmaceutically acceptable anionxe2x80x9d refers to an anion that has little or no toxic effect and does not significantly influence the pharmacological action of a pharmaceutically administered dose. Examples include chloride, bromide, iodide, nitrate, sulfate, phosphate, sulfonate, mesylate, besylate, tosylate, and the like.
A variety of optical isomers, enantiomeric pairs, and diastereomeric pairs exist for many of the compounds within the scope of the present invention. All such compounds are intended, as are all mixtures of optical isomers, enantiomeric pairs and diastereomeric pairs, for each structural variation, including all pure compounds and racemic mixtures.
Both cis and trans geometrical isomers and mixtures are intended.
Syntheses
There will now be described various synthetic pathways for preparing the compounds of the present invention. These pathways will be illustrated using N-methyl-8-azabicyclo [3.2.1]octan-3xcex1-ol (tropine) as an example of the starting material. Other suitable cyclic aminoalkanols can be used as well.

Referring to eq. A of Synthetic Pathway A, the procedure is carried out as follows. To a cooled solution of one equivalent of the appropriate diacyl halide (II) in dry methylene chloride in an ice bath is added dropwise two equivalents of tropine in dry methylene chloride, and then the mixture is allowed to warm up to room temperature. After the reaction mixture is poured into the cold water, the aqueous layer is adjusted to pH 10-11 with 6N NaOH aqueous solution, and extracted with chloroform. The diester (III) is then purified by a chromatographic technique.
In eq. B, one equivalent of the purified diester (III) is taken up in a moderately polar aprotic solvent, such as acetone or acetonitrile. Two and one-half equivalents of the appropriate alkoxy, acyloxy or alkoxyacyloxy substituted aralkyl or aralkenyl halide, RX (IV) are added. The resulting solution is heated at between 50xc2x0 C. and 150xc2x0 C. for 6 to 12 hours depending on the reactants. The resulting quaternary salts are filtered, and purified by recrystallization.

Referring to eq. C of Synthetic Pathway B, in an alternative synthetic pathway one equivalent of the appropriate tropine (I) and one and one-quarter equivalents of the desired alkoxy, acyloxy or alkoxyacyloxy substituted aralkyl or aralkenyl halide (IV) are heated together in a moderately polar aprotic solvent, such as acetone or acetonitrile, for between 6 and 12 hours at between 50xc2x0 C. and 100xc2x0 C. The resulting quaternary ammonium salt (V) is filtered and purified by recrystallization.
Then, as shown in eq. D, two equivalents of the recrystallized quaternary salt (V) are reacted with one equivalent of the appropriate organic diacyl halide (II) in dry methylene chloride in a sealed vessel. The ingredients are heated in a closed vessel at 80-100xc2x0 C. After the solvent is removed, the residue is purified by recrystallization and pure compound of Formula 1/a, 1/b and 1/c are obtained.
The compounds of Formula 1/a-1/c of this invention can also be asymmetrical diammonium esters. These compounds are made by the following method: No more than one equivalent of a first, alkoxy or acyloxy substituted aralkyl or aralkenyl halide (RX) and one equivalent of diester (III) in acetone or acetonitrile are heated at 50xc2x0 C. for 12hours; To the reaction mixture is added a second, quaternizing compound, RX (IV). Then the reaction mixture is heated again at 80-100xc2x0 C. for 12 hours. The resulting precipitate is purified by recrystallization.
An alternative to synthetic pathway A is illustrated in Synthetic Pathway C.

Other suitable cyclic aminoalkanol hydrochlorides, such as tropine hydrochloride or granatanol hydrochloride, can be used as well.
Utility
The compounds of Formulae 1/a, 1/b and 1/c show marked activity as neuromuscular blocking agents. Such agents are typically administered intravenously. The form of administration can be a single injection, a series of injections, or the agent can be given as a component of an intravenous infusion. The compounds of this invention are characterized by rapid onset and short duration of action to the extent that they are clearly superior to any existing known muscle relaxants. Regarding side effects, the compounds of this invention have markedly reduced cardiovascular side effects associated with succinylcholine, tubocurarine or gallamine, the earlier prototypes of clinically used muscle relaxants.
The bolus dosage may vary markedly between each individual patient as it does with other muscle relaxants, but generally, as estimated on the basis of animal experiments, the dose will be between 0.1 and 1.0 mg/kg of body weight. The precise dose must be arrived at after having considered each individual case, including age, sex, weight and general condition of the patient and the degree of muscle relaxation desired.
The form of dosage can be liquid solution, either for direct injection or for addition to an intravenous fluid, or it can be a solid powder or granular material to be made into a solution prior to use. The liquid or solid can be formulated by any conventional means.
One or more pharmaceutically acceptable excipients or adjuvants may be included in a clinical formulation, including pH modifiers, stabilizers, preservatives, biologically necessary salts, sugars, and the like.
The activity of these compounds can be tested by any of several methods.
The utility of the compounds of Formulae 1/a, 1/b and 1/c have been tested by using anesthetized rats and/or cats, rabbits, dogs, guinea pigs, pigs, or monkeys. A leg tendon is attached to a transducer. An appropriate motor nerve, e.g. the sciatic or common peroneal nerve is stimulated. The resultant muscle twitches are transduced and recorded. As the neuromuscular blocking agents of this invention are administered into a vein, the muscle twitch response to the stimulation decreases. This dose-dependent decrease is measured. Likewise, the onset and duration of this action can be determined, and compared with those of known, clinically used agents. Electromyographic and mechanomyographic methods are both acceptable.
The invention will be better understood by reference to the following examples which are included merely for purposes of illustration and are not to be construed as limiting the scope of the present invention.
The following example illustrates Synthetic Pathway A.